Self assembled nanostructures are a class of materials having chemical and physical properties attractive for drug formulation, administration and delivery applications. Amphiphilic polymer micelle supramolecular structures, for example, are capable of encapsulating and facilitating the solubilization of poorly water soluble drugs, including extremely hydrophobic pharmaceutical compositions. Encapsulation of drugs by amphiphilic polymer self assembled micelle nanostructures also has benefits for reducing toxicity and stabilizing therapeutic agents under administration and delivery conditions. Incorporation of targeting ligands into amphiphilic polymer micelle delivery systems also has potential for enabling directed delivery of pharmaceuticals to specifically targeted cells, tissues and organs.
Amphiphilic polymer micelles are formed via entropically driven self assembly processes of amphiphilic polymers, including block copolymers, having spatially segregated hydrophilic and hydrophobic domains. For example, when amphiphilic polymers are provided in aqueous solution at a concentration above critical micelle concentration (CMC) the polymers aggregate and self align such that hydrophobic domains form a central hydrophobic core and hydrophilic domains self align into an exterior hydrophilic corona region exposed to the aqueous phase. The core-corona structure of amphiphilic polymer micelles provides useful physical properties, as the hydrophobic core provides a shielded phase capable of solubilizing hydrophobic molecules, and the exterior corona region is at least partially solvated, thus imparting colloidal stability to these nanostructures. Amphiphilic polymer micelles typically exhibit a spherical geometry and may have substantially uniform nanoscale cross sectional dimensions ranging from about 10 nanometers to about 100 nanometers. These physical dimensions are large enough to allow for effective loading and stabilization of hydrophobic molecules, such as drugs, into the hydrophobic core of amphiphilic polymer micelles. Amphiphilic polymer micelle nanostructures are small enough, however, to allow their effective circulation in the blood for prolonged periods. Micelle compositions are also subject to low mononuclear phagocyte uptake and low levels of renal excretion. In addition, amphiphilic polymers of these structures are typically small enough so that upon dissociation of the micelles they are effectively eliminated by the kidney, thus avoiding potentially deleterious buildup of micelle components in the liver. As a result of this combination of attributes, amphiphilic polymer micelles are rapidly emerging as a preferred class of nanomaterials for delivering low-solubility, highly hydrophobic drugs, such as anti-cancer drugs, and antifungal agents.
A number of amphiphilic polymers, including block copolymers, have been specifically designed and developed for drug delivery and formulation applications. The following references provide examples of amphiphilic polymer drug delivery systems, including block copolymer drug delivery systems, which are hereby incorporated by reference in their entireties; Kwon, G. S.; Naito, M.; Kataoka, K.; Yokoyama, M.; Sakurai, Y.; Okano, T. “Block Copolymer Micelles as Vehicles for Hydrophobic Drugs” Colloids and Surfaces, B: Biointerfaces 1994, 2, 429-34; Torchilin, V. P. “Structure and Design of Polymeric Surfactant-Based Drug Delivery Systems” J. Controlled Release 2001, 73, 137-172; Kwon, G. S. “Polymeric Micelles for Delivery of Poorly Water-Soluble Compounds” Crit. Rev. Ther. Drug Carrier Syst. 2003, 20, 357-403; Adams, M. L.; Lavasanifar, A.; Kwon G. S. “Amphiphilic Block Copolymers for Drug Delivery” J. Pharm. Sci. 2003, 92, 1343-1355; Jones, M. -C.; Leroux J. -C.; “Polymeric Micelles: A New Generation of Colloidal Drug Carriers” Eur. J. Pharm. Biopharm. 1999, 48, 101-111; 36. Burt, H. M.; Zhang, X.; Toleikis, P.; Embree, L.; Hunter, W. L. “Development of Copolymers of poly(D,L-lactide) and Methoxypolyethylene Glycols as Micellar Carriers of Paclitaxel” Coll. Surf. B Biointerfaces. 1999, 16, 161-171; Lavasanifar, A.; Samuel, J.; Kwon G. S. “Poly(ethylene oxide)-block-poly(L-amino acid) Micelles for Drug Delivery” ”. Adv. Drug Del. Rev. 2002, 54, 169-190; and Lavasanifar, A.; Samuel, J.; Kwon G. S. “The Effect of fatty Acid Substitution on the in vitro Release of Amphotericin B from Micelles Composed of poly(ethylene oxide)-block-poly(N-hexyl stearate-L-aspartamide” J. Control Release 0.2003, 87, 23-32).
Poly(ethylene glycol) (PEG) is a widely used hydrophilic, corona-forming segment. PEG-based amphiphilic polymers developed for drug delivery including PEG-poly(ε-caprolactone), PEG-poly(amino acid), PEG-polylactide and a variety of a PEG—phospholid constructs, such as PEG-distearoylphosphatidylethanolamine. Use of PEG-containing amphiphilic polymers has been demonstrated to have a number of significant benefits. First, PEG is considered to have biocompatible properties and its incorporation in amphiphilic polymer micelles confers lower toxicity to these nanostructures. Second, incorporation of a PEG hydrophilic component into amphiphilic polymer micelle nanostructures has been shown to reduce uptake by the reticuloendothelial system. Finally, PEG hydrophilic segments are capable of conjugation to a variety of different hydrophobic polymers via a number of conventional synthetic pathways. Other hydrophilic groups portions have been pursued for enhancing amphiphilic polymer micelle stability including cross linked systems, such as use of a cross linked poly(acrylic acid) corona component [Thurmond, K. B.; Huang, H. Y; Clark, C. G.; Kowalewski, T.; Wooley, K. L. Coll. Surf. B. 1999.16, 45-54] and use of a cross linked poly(amino acid) corona component [U.S. Pat. Pub. No. 2006/0240092].
Despite significant advances in the development of micelle delivery systems significant challenges remain that limit clinical adoption of this technology. In vivo stability is an important factor for effective micellar drug delivery. Micelles experience conditions of extreme dilution upon intravenous delivery that often reduces the concentration of block copolymers to well below critical micelle concentration. Such dilution consequently initiates rapid dissociation of the micelles, thereby resulting in loss of therapeutic cargo prior to delivery to cells and tissue of interest. Accordingly, the critical micelle concentration of amphiphilic polymers for micelle delivery systems is of great importance to effective clinical implementation. In addition, interactions with blood components, such as proteins, lipids and carbohydrates, can also destabilize micelles under in vivo conditions. These interactions can result in loss and/or premature release of therapeutic cargo outside the targeted region, thereby reducing the efficiency or rendering ineffective micelle drug delivery systems. To address these challenges, several strategies to mitigate premature dissociation of the micelles have been pursued.
Modifications of the hydrophobic segment of the amphiphilic polymer can induce a radical change in the assembly behavior of the micelle. For instance, attaching two hydrophobic chains to the same end of the hydrophilic segment is known to have the potential of generating a bilayer that can eventually close into a vesicle. This is a commonly observed case for phospholipids when the hydrophilic section of the amphiphile is of comparable size to the phospholipid. Vesicles or liposomes are very stable, but they can be ten times bigger than micelles, and difficult to functionalize. They can also create problems in the mechanisms of excretion from the organism in which they are injected. More importantly, the interior of a liposome is not hydrophobic as both the external and internal surfaces of such an aggregate are lined with hydrophilic groups.
Other approaches for stabilizing micelle systems for drug delivery include formulations having stabilizing additives, such as stabilizers, surfactants and excipients. Additives for enhancing micelle stability may be capable of integrating into hydrophilic and/or hydrophobic regions of the micelle structure so as enhance stability during delivery, for example by reducing the extent of destabilization by protein-micelle interactions.
A more common strategy for stabilizing micelles consists of using hydrophobic segments that contain functional groups able to interact, and therefore bind, the encapsulated drug. Examples of substituted hydrophobic segments pursued for micelle drug delivery applications include poly(β-substituted aspartate), poly(γ-substituted glutamate) and poly(L-leucine). While this approach can be effective in some specific cases, it should be noted that functionalization of the hydrophobic segment of an amphiphilic molecule often results in a significant decrease in its hydrophobicity, therefore increasing the critical micelle concentration. Accordingly, a trade-off exists in the functionalization of hydrophilic portions of amphiphilic polymers for micelle drug delivery between achieving effective molecular recognition/drug binding and retaining a degree of hydrophobicity necessary for stable micelle-mediated drug delivery. As a consequence, micelles that are able to encapsulate and deliver specific compounds are currently limited in number and only work for very specific compounds under relatively narrow delivery conditions.
U.S. Patent Publication US2005/0214379 (Mecozzi et al.) published on Sep. 29, 2005 describes an alternative approach wherein a block copolymer having a perfluorinated or semifluorinated block is used for micelle drug delivery. As reported by the authors, fluorination, particularly perfluorination, can have a significant impact on the physical and chemical properties of organic molecules. Incorporation of a perfluorinated component to a block copolymer, for example, can result in formation of a fluorous phase, that does not readily mix with both polar and/or non-polar hydrogenated phases. Perfluorinated polymers also have a low surface energy, they are both lipo- and hydrophobic, and they are often unsurpassed in their high chemical and thermal stabilities. Applicability of the disclosed perfluorinated or semifluorinated block copolymers for encapsulation and administration of a variety of fluorine containing therapeutic compositions, including sevoflurane, is reported in Mecozzi et al. In an embodiment, block copolymers having a perfluorinated block are provided at a concentration larger than the critical micelle concentration so as to form stable supramolecular structures capable of encapsulating fluorophilic chemical compounds. The authors report that the fluorinated or perfluorinated block copolymers self assemble into micelles wherein the fluorinated or semifluorinated blocks of the copolymer orient toward and surround a fluorous core of the fluorine containing therapeutic composition. A variety of block copolymer compositions are reported as useful for administration of fluorinated therapeutic compositions, including dual block copolymers having a poly(ethylene glycol) block and a perfluorinated alkane block.
U.S. patent application Ser. No. 11/946,174, filed on Nov. 28, 2007, describes formulations capable of generating a nanoemulsion of a large amount of a fluorinated volatile anesthetic dispersed in an aqueous solution. Formulations of this reference include surfactants, such as semi-fluorinated block copolymers having a hydrophilic block and a fluorophilic block that are capable of self-assemble upon emulsification to form supramolecular structures dispersed in an aqueous continuous phase that encapsulate and stabilize significant quantities of the fluorinated volatile anesthetic component in a fluorous inner droplet core. The formulations in U.S. patent application Ser. No. 11/946,174 also include one or more stabilizing additives, such as one or more perhalogenated fluorocarbons, that enhance stability with respect to droplet size by decreasing the rate of Ostwald ripening, coagulation and/or phase separation processes.
It will be appreciated from the foregoing that polymer compositions for micelle delivery systems are needed for the administration and formulation of insoluble and/or toxic pharmaceutical compositions. Micelle delivery systems and formulations providing enhanced stability under delivery conditions are required for a variety of clinical applications. Amphiphilic polymers exhibiting a low critical micelle concentration, low toxicity and a high degree of biocompatibility are needed to enable practical implementation of micelle mediated drug delivery.